UC Irvine

Nicotinic acetylcholine receptor (nAChR) activation has been shown to improve sensory-cognitive function. In the auditory system, nicotine (an agonist of nAChRs) enhances the brain’s response to attended, relevant stimuli while reducing the response to distracters. Activation of nAChRs has a similar ability to improve stimulus detection in other sensory systems and while it is a remarkable and consistent finding, there is a lack of comprehensive studies on the neural activity behind this phenomenon. Using the mouse auditory system as a model, here we test the role of nAChRs in auditory processing, specifically spectral processing, and the underlying cortical circuitry driving nicotine’s effects.

In Chapter 1, we used a tone-in-notched-noise stimulus to examine how nicotine influences the ability to filter incoming frequency information. Current-source density recordings in the primary auditory cortex of the anesthetized mouse revealed that systemic nicotine effectively narrows receptive fields, increases response gain in the center of the receptive field, and enhances responses to the tone. Subsequent manipulations demonstrated that modulation of cortical receptive fields and tone-evoked responses occurred at multiple levels in the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to the nicotinic enhancement of sensory and cognitive processing.

In Chapter 2, we performed whole-cell recordings in the auditory cortex of mouse brain slices to investigate the role of discrete cell types. Bath application of nicotine selectively depolarized pyramidal (Pyr) and vasoactive intestinal peptide (VIP)- containing neurons and enhanced spontaneous inhibitory post-synaptic currents (sIPSC) in Pyr, VIP, and SOM cells. We found that VIP cell activation is responsible for both the nicotinic depolarization and sIPSC enhancement observed in Pyr neurons, implicating a disinhibitory neural circuit in the nicotinic modulation of cortex. This disinhibition likely renders Pyr cells more excitable and responsive to incoming stimuli, thus providing a probable mechanism for nicotine’s beneficial effects on cortical processing and function.

Together with the findings in Chapter 1, these results further reveal the neural basis of nicotine’s effects and substantiate efforts to use nicotine as a therapeutic for those with cognitive or sensory processing disorders.